Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to a class of compounds having antimycoplasmal and antibacterial activity, to processes for their preparation and to their use in human and veterinary medicine and also to intermediates for use in the preparation of such compounds.
• R0 denotes a group of the formula (a), (b) or (c): in which formulae R1, R2, and R3 may be the same or different and each is selected from hydrogen, halogen, optionally substituted (C1 ⁇ 6)alkyl, aryl, aralkyl, heterocyclyl, (C1 ⁇ 6)alkoxy, hydroxy, carboxy and salts thereof, (C1 ⁇ 6)alkoxycarbonyl, carbamoyl, mono- or di-(C1 ⁇ 6)alkylcarbamoyl, sulphamoyl, mono- and di-(C1 ⁇ 6)alkylsulphamoyl, cyano, nitro, amino, mono- and di-(C1 ⁇ 6)alkylamino, acylamino, ureido, (C1 ⁇ 6)­alkoxycarbonylamino, (C1 ⁇ 6)alkoxyimino, 2,2,2-trichloroethoxycarbon
• R0 is a group of formula (a) and R1 is preferably hydrogen and R2 preferably (C1 ⁇ 6)alkyl or R0 is a group of formula (b) and R1 and R3 are preferably hydrogen and R2 preferably cyano.
• R1 and R3 is each hydrogen.
• the term 'aryl' includes for example phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, optionally substituted (C1 ⁇ 6)alkyl, phenyl, (C1 ⁇ 6)alkoxy, halo(C1 ⁇ 6)alkyl, hydroxy, amino, mono- or di-(C1 ⁇ 6)alkylamino, nitro, carboxy, (C1 ⁇ 6)alkoxycarbonyl, optionally substituted (C1 ⁇ 6)alkoxycarbonyl(C1 ⁇ 6)alkyl, (C1 ⁇ 6)alkylcarbonyloxy, (C1 ⁇ 6)alkylcarbonyl, (C1 ⁇ 6)alkylthio, (C1 ⁇ 6)alkanesulphinyl, and (C1 ⁇ 6)alkanesulphonyl.
• halogen optionally substituted (C1 ⁇ 6)alkyl, phenyl, (C1 ⁇ 6)alkoxy, halo(C1 ⁇ 6)alkyl,
• 'aralkyl' includes groups in which the aryl moiety is a phenyl group which may be optionally substituted as herein before defined for aryl and in which the alkylene radical has from 1 to 4 carbon atoms.
• heterocyclyl' includes for example single or fused rings comprising up to four hetero atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three groups selected from halogen, optionally substituted (C1 ⁇ 6)alkyl, (C1 ⁇ 6)alkoxy, halo(C1 ⁇ 6)alkyl, hydroxy, amino, mono- or di(C1 ⁇ 6)alkylamino, carboxy, (C1 ⁇ 6)alkoxycarbonyl, (C1 ⁇ 6)alkoxycarbonyl(C1 ⁇ 6)alkyl, aryl or oxo.
• halogen optionally substituted (C1 ⁇ 6)alkyl, (C1 ⁇ 6)alkoxy, halo(C1 ⁇ 6)alkyl, hydroxy, amino, mono- or di(C1 ⁇ 6)alkylamino, carboxy, (C1 ⁇ 6)alkoxycarbonyl, (C1 ⁇ 6)alkoxycarbonyl(C1 ⁇ 6)alkyl, aryl or oxo.
• heterocyclic ring comprises from 4 to 7 ring atoms, preferably 5 or 6 atoms.
• 'halogen' refers to fluorine, chlorine, bromine or iodine.
• Suitable substituents for alkyl include for example halogen, hydroxy, ( C1 ⁇ 6)alkoxy, carboxy and salt thereof, (C1 ⁇ 6)alkoxycarbonyl, carbamoyl, mono- or di(C1 ⁇ 6)alkylcarbamoyl, sulphamoyl, mono- and di(C1 ⁇ 6)alkylsulphamoyl, amino, mono- and di(C1 ⁇ 6)alkylamino, (C1 ⁇ 6)acylamino, ureido, (C1 ⁇ 6)­alkoxycarbonylamino, 2,2,2-trichloroethoxy­carbonylamino, aryl, heterocyclyl, oxo, acyl, 2-thenoyl, (C1 ⁇ 6)alkylthio, arylthio, (C1 ⁇ 6)­alkanesulphinyl, arylsulphinyl, (C1 ⁇ 6)alkanesulphonyl, arylsulphonyl, (C
• R1, R2, or R3 may contain one or more chiral centres.
• the present invention encompasses all such resultant isomeric possibilities.
• Specific compounds within this invention include the following: 2-(1-normon-2-yl)-5-(3-phenylisoxazol-5-yl)oxazole; 2(1-normon-2-yl)-5-(3-p-methylthiophenylisoxazol-5-yl)­oxazole; 2-(1-normon-2-yl)-5-(3-p-methylsulphonylphenylisoxazol-­5-yl)oxazole; 2-(1-normon-2-yl)-5-(3-methylisoxazol-5-yl)oxazole; 5-(3-bromo-5-isoxazolyl)-2-(1-normon-2-yl)oxazole; 2-(1-normon-2-yl)-5-(3-methoxy-5-isoxazolyl)oxazole; 2-(1-normon-2-yl)-5-(3-isopropyl-5
• the present invention provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (III): in which Z1, Z2 and Z3 are the same or different and each is hydrogen or a hydroxyl-protecting group, with a compound of formula (IV): in which: R0 is as defined in relation to formula (I); M+ is a metal cation, preferably an alkali metal cation, most preferably a lithium or sodium cation, and; R4 is an anion-stabilising group which will spontaneously eliminate with a ⁇ -hydroxyl group to produce an olefin, preferably a trialkylsilyl or a dialkylphosphonate group, most preferably trimethylsilyl or diethylphosphonate; and, where necessary, removing any hydroxyl-protecting groups, and, if desired, converting one compound of formula (I) into a further compound of formula (I).
• reaction of a compound of formula (III) with a compound of formula (IV) may conveniently be effected in an organic solvent, such as tetrahydrofuran, diethyl ether or dimethyl sulphoxide, at from reduced to elevated temperature, such as from -80 o to 100 o C.
• organic solvent such as tetrahydrofuran, diethyl ether or dimethyl sulphoxide
• the compounds of formula (IV) may be produced by conventional processes such as described in EP-A-0 123 378 and shown in Scheme I.
• R0 is a 5-isoxazolyl group
• a convenient synthetic strategy takes as its starting point a 5-acetyl-isoxazole which is either commercially available or well known or prepared from readily available starting materials by adaptation of conventional methodology.
• the 5-acetyl substituent can be manipulated using procedures similar to those described in Organic Synthesis ; Coll. Vol. V, 909, to give an ⁇ -aminoketone of formula (VI): in which R1 and R2 are as hereinbefore defined.
• ⁇ -amino ketone functionality can then be used to form an oxazole ring, according to the methodology described by J.L. La Mattina, J . Org . Chem ., 1980, 45 , 2261.
• the present invention also provides a process for the preparation of a compound of formula (I) which process comprises cyclising a compound of formula (VII): in which R0 is as defined in relation to formula (I), and Z1, Z2 and Z3 are the same or different and each is hydrogen or a hydroxyl-protecting group; to form a compound of formula (I) and, where necessary, removing any hydroxyl-protecting groups, and, if desired, converting one compound of formula (I) into a further compound of formula (I).
• the cyclisation of a compound of formula (VII) is suitably effected using a chlorinating agent such as phosphorus oxychloride, phosgene, thionyl chloride or phosphorus pentachloride in the presence of a tertiary amine, such as triethylamine or pyridine.
• a chlorinating agent such as phosphorus oxychloride, phosgene, thionyl chloride or phosphorus pentachloride
• a tertiary amine such as triethylamine or pyridine.
• Such reactions are conveniently effected in an organic solvent, for instance dichloromethane or tetrahydrofuran, at from reduced to elevated temperature, for instance -80 o to 100 o C, over a period of several hours to a few days.
• phosgene or phosphorus oxychloride is used, at a temperature of from 0 o to 20 o C.
• cyclisation may be effected using triphenylphosphine and carbon tetrachloride as the chlorinating reagent, in the presence of a tertiary amine, for instance triethylamine, in an inert solvent such as acetonitrile or acetonitrile-pyridine.
• a tertiary amine for instance triethylamine
• an inert solvent such as acetonitrile or acetonitrile-pyridine.
• Compounds of formula (VII) may also be cyclised using a carboxylic anhydride or mixed anhydride or acid chloride, such as trifluoroacetic anhydride or trichloroacetic anhydride or trichloroacetyl chloride which latter is used in the presence of pyridine and 4-dimethylaminopyridine.
• a carboxylic anhydride or mixed anhydride or acid chloride such as trifluoroacetic anhydride or trichloroacetic anhydride or trichloroacetyl chloride which latter is used in the presence of pyridine and 4-dimethylaminopyridine.
• Trihaloacetyl groups formed during cyclisation may be removed using potassium carbonate in solvents such as water, alkanols or admixtures thereof. Appropriate deprotecting conditions for removing other acyl residues will be readily apparent to the skilled person.
• the hydroxy groups of the 1-normon-2-yl radical may be protected, prior
• the present invention also provides a compound of formula (VII), as hereinbefore defined.
• the present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula (VIII): in which: Z1, Z2, and Z3 are the same or different and each is hydrogen or a hydroxyl-protecting group, R0 is as hereinbefore defined, and Y is a leaving group; with a strong base, and thereafter removing, if necessary, any hydroxyl-protecting groups.
• Suitable values for Y include, for instance, aryl sulphonyl, for example p -toluenesulphonyl, alkylsulphonyl, alkyl or aryl sulphinyl, quaternary ammonium, for example trialkylammonium, and dialkoxy phosphine oxide.
• Suitable strong bases include for example 1,8-diazo­bicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazo­bicyclo[4.3.0]non-5-ene (DBN).
• DBU 1,8-diazo­bicyclo[5.4.0]undec-7-ene
• DBN 1,5-diazo­bicyclo[4.3.0]non-5-ene
• the reaction is effected in a solvent such as acetonitrile, and at a temperature in the range from -20 to +80 o C.
• a solvent such as acetonitrile
• the present invention also provides a compound of formula (VIII), as hereinbefore defined.
• Compounds of formula (VIII) may be prepared by the treatment of a compound of formula (IX): in which Z1, Z2, and Z3 are the same or different and each is hydrogen or a hydroxyl-protecting group, and Y is as hereinbefore defined, with a compound formula (X): R0CHO (X) in which R0 is as hereinbefore defined, or a corresponding analogue thereof in which the aldehyde functionality of the compound formula (X) is masked, under dehydrating conditions.
• Suitable dehydrating conditions are similar to those hereinbefore described in respect of the cyclisation of a compound of formula (VIII) to give a compound of formula (I).
• Particularly suitable conditions include the use of triphenylphosphine in combination with carbon tetrachloride or hexachloroethane, in the presence of triethylamine.
• the present invention also provides a compound of formula (IX) as hereinbefore defined.
• Compounds of formula (X) are recognisable as aldehyde derivatives of furans and isoxazoles and are either available commercially or well known or prepared from readily available starting materials by the adaptation of standard methodology.
• a compound of formula (IX) may be prepared from an amide of formula (XI): in which Z1, Z2, and Z3 are the same or different and each is hydrogen or a hydroxyl protecting group, by application of conventional methodology.
• an amide of formula (XI) may be treated with formaldehyde in the presence of an aryl or an alkylsulphonic acid (in the instance when is aryl- or alkylsulphonyl).
• an amide of formula (XI) may be treated with either N,N,N,N-tetramethylmethylene diamine or N,N-dimethylmethylene-ammonium iodide (Eschenmoser's salt), followed by quaternisation of the intermediate amine and then treatment with an aryl- or alkylsulphonic acid (in the instance when Y is aryl- or alkylsulphonyl).
• a compound of formula (I) may also be prepared from compound of formula (XII): in which R0, Z1, Z2 and Z3 are as hereinbefore defined; by methods known for the isomerisation of a carbon-carbon double bond.
• Suitable isomerisation methods are described by Sonnet in Tetrahedron , 1980, 36 , 557 and include photo­chemical and addition-elimination methods.
• a compound of formula (XII) may be prepared by treatment of a compound of formula (III) with a compound of formula (IV), as hereinbefore described. This reaction may lack stereoselectivity and may lead to the formation of compounds of formulae (I) and (XII), which may then be separated by conventional procedures such as chromatography.
• the present invention also provides a compound of formula (XII) as hereinbefore defined.
• Conversion of one compound of formula (I) to another compound of formula (I) may be effected by conventional methods.
• all or any of R1, R2, and R3 may be modified or converted. Included within modification of R1, R2, and R3 are salification and esterification of a carboxy substituent, trans- and de-esterification of an ester-containing substituent, reduction of an alkoxycarbonyl substituent and formation of the free carboxy group from a carboxylate salt.
• Another example of such conversion is the formation of alkanesulphinyl and alkanesulphonyl compounds from the corresponding alkylthio compound of formula (I). This latter conversion may be achieved using conventional oxidising agents such as percarboxylic acids, for instance m-chloroperbenzoic acid, in a suitable solvent.
• hydroxyl-protecting group' refers to any such group known in the art which may be removed without disruption of the remainder of the molecule. Suitable hydroxyl-protecting groups include those described in Protective Groups in Organic Synthesis, T.W. Greene, Wiley-Interscience, New York 1981.
• hydroxyl groups of monic acid and the compounds of formulae (III), (IX), (XI) and (XII) may be protected at any stage of the above processes, using conventional methods.
• the hydroxyl-protecting group may be removed by methods known in the art, including enzymatic methods.
• Particularly suitable protecting groups are silyl groups since these are readily removed under mild conditions.
• a preferred silyating agent is trimethylsilyl chloride.
• Particularly suitable protecting groups are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups.
• Preferred protecting groups are trimethylsilyl groups because of their ease of removal.
• the glycol function of monic acid and the compounds of formulae (III), (IX), (XI) and (XII) may be protected by forming a cyclic derivative using a compound of formula (XIII): wherein R6 is hydrogen or (C1 ⁇ 6)alkyl and each of R6, R7 and R8 is (C1 ⁇ 6)alkyl.
• R6 is hydrogen or (C1 ⁇ 6)alkyl and each of R6, R7 and R8 is (C1 ⁇ 6)alkyl.
• Z1 and Z2 together are a moiety: wherein R9 is (C1 ⁇ 6)alkyl.
• R5 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen.
• the groups R6, R7 and R8 are suitably methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or t-butyl; most suitably methyl.
• the protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K. Luk and N.H. Rogers, in 'Chemistry of Pseudomonic Acid, Part II', J.C.S. Perkin Trans. I , 1979, 308.
• the compounds of this invention are useful for the treatment of bacterial infections in animals, including man, such as respiratory tract infections, otitis, meningitis, and skin and soft tissue infections in man, and mastitis in cattle and respiratory infections in animals such as pigs and cattle.
• the compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus for instance H.influenzae Q1; Branhamella , for instance B.Catarrhalis 1502; Streptococci , for instance S.pyogenes CN10 and S.pneumonia PU7; and Staphylococci for instance S.aureus Oxford.
• Haemophilus for instance H.influenzae Q1
• Branhamella for instance B.Catarrhalis 1502
• Streptococci for instance S.pyogenes CN10 and S.pneumonia PU7
• Staphylococci for instance S.aureus Oxford.
• This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.
• a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.
• compositions may be formulated for administration by any route, and would depend on the disease being treated.
• the compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p -hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or acacia
• non-aqueous vehicles which may include edible oils
• almond oil fractionated coconut oil
• oily esters such as glycerine,
• Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, and the British Pharmacopoeia.
• Suppositories will contain conventional suppository bases, e.g. cocoa-butters or other glyceride.
• fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle.
• the drug depending on the vehicle and concentration used, can be suspended in the vehicle.
• adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial.
• the drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.
• the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.
• a suitable liquid carrier such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.
• the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle.
• Additives for instance buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
• compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg of the drug.
• Veterinary compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis will generally contain a suspension of the drug in an oily vehicle.
• compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the drug, depending on the method of administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg, of the drug.
• the dosage as employed for adult human treatment will preferably range from 100 mg to 3 g, per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.
• the drug may be administered as part of the total dietary intake.
• the amount of drug employed may be less than 1% by weight of the diet and in preferably no more than 0.5% by weight.
• the diet for animals may consist of normal foodstuffs to which the drug may be added or the drug may be included in a premix for admixture with the foodstuff.
• a suitable method of administration of the drug to animals is to add it to the animals' drinking water. In this case a concentration of the drug in the drinking water of about 5-500 ⁇ g/ml, for example 5-200 ⁇ g/ml, is suitable.
• the present invention further provides a method for treating the human or non-human animal which method comprises administering an effective amount of a compound of formula (I) to a human or non-human animal in need of such therapy.
• compositions as hereinbefore described may be employed in the treatment.
• HP2055 is a grade of DIAION HP20 (Trade Mark) styrene-divinylbenzene copolymer resin.
• Monic acid A is obtained from pseudomonic acid according to the process described in GB 1 587 058
• t-Butyldimethylsilyl trifluoromethane sulphonate (1.30ml, 5.7mmol) was added to a solution containing 3,4-dihydroxy-5-(2,3-epoxy-5-hydroxy-4-methylhexyl)­tetrahydropyran-2-yl acetone (0.36g, 1.2mmol), 2,6-­lutidine (1.1ml, 10mmol), and THF (10ml) at -20 o C. After 30min at -20 o C aqueous ammonium chloride and ethyl acetate were added.
• Trichloroacetyl chloride (9 equiv.) was added to a solution of a monamide, 4-dimethylaminopyridine (few crystals/mmol) and pyridine (20 equiv.) in dichloro­methane (10ml/mmol), cooled in an ice bath. After 0.5h the solution was washed with aqueous sodium hydrogen carbonate solution and then evaporated under reduced pressure. The resulting residue was dissolved in methanol (5ml/mmol) and the solution cooled to 0 o C before addition of potassium carbonate (3 equiv.). After 15min at 0 o C brine and ethyl acetate were added and the organic layer separated.
• reaction mixture was partitioned between ethyl acetate and halfsaturated brine.
• the aqueous phase was further extracted with ethyl acetate and the combined organic extracts were dried (MgSO4) and evaporated affording a dark brown foam (0.4g).
• Chlorine (12g, 0.17mmol) was added to acetaldoxime (10g, 0.17mmol) in hydrochloric acid (40ml, 1.5M) at -5 o C. Saturated aqueous ammonium sulphate was then added and the solution extracted with ether. The combined extracts were added during 30min to a well stirred mixture of potassium hydrogen carbonate (44g, 0.45mmol), but-2-yn-1-ol (18ml, 0.30mmol), ethyl acetate (600ml), and water (6ml).
• Eschenmoser's salt N,N-dimethylmethylene­ammonium iodide, 0.4g, 2.0mmol was added to a solution of tris (trimethylsilyl)monamide (1.0g, 1.8mmol) in tetrahydrofuran (20ml) at 20 o C. After 1h at 20 o C the solution was partitioned between aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was dried (MgSO4) and evaporated and the residue purified by chromatography (silica, methanol/dichloro­methane) to give the title compound identical to that prepared above (0.8g, 72%).
• Carbon tetrachloride (0.15ml, 1.5mmol) was added to a solution containing the above tris (trimethylsilyl) N-­tosylmethylmonamide (90mg, 0.12mmol), 3-methyl­isoxazole-5-carboxaldehyde (33mg, 0.30mmol), triphenyl­phosphine (120mg, 0.45mmol), triethylamine (0.09ml, 0.60mmol), and acetonitrile (1ml) at 20 o C.
• 3-Bromoisoxazole-5-carboxylic acid (5g, 26mmol) and pyrrolidine (50ml, 600mmol) were refluxed at 80 o C for 66h then added slowly to 5 M hydrochloric acid (125ml) to give a resulting pH of 2.
• the product was extracted using diethyl ether, the organic layer separated, dried (MgSO4), and evaporated to give 3-(1-pyrrolidinyl)­isoxazole-5-carboxylic acid as white rhombs (2.31g, 49%); ⁇ H (CDCl3) 2.0 (4H, m, CH2), 3.3 (4H, M, N-CH2) and 6.45 (1H, s, isoxazole).
• Bromine (2.1ml) was added to a solution of 2-­acetylfuran (5.5g) in ether (100ml). When no bromine colour was present the solution was washed with sodium hydrogen carbonate solution, brine, then dried (MgSO4) and quickly reduced to an oil. The oil was dissolved in methylene chloride (25ml) was stirred at room temperature for 1h with hexamethylene tetramine (7g). The product was filtered off and washed with methylene chloride then dried and redissolved in ethanol (40ml) - conc. hydrochloric acid (20ml).
• Trichloroacetyl chloride (0.22ml, 4.5 eq.) was added to a solution of the monamide derivative (200mg) [prepared in (b)] in methylene chloride (20ml), pyridine (0.22ml, 6 eq.) and DMAP (few crystals) at 0 o C. After 1h the solution was evaporated to dryness and the residue dissolved in methanol (30ml) and treated with potassium carbonate (0.44g, 6 eq.) and a few drops of water. The reaction was stirred at room temperature overnight then evaporated to dryness and the residue dissolved in ethyl acetate which was washed with brine.
• This ketoamide (1.4g) was cyclised to give the oxazole (550mg, 40.6%) after column chromatography on silica (methanol in dichloromethane gradient); ⁇ max (film) 3390 and 1660cm ⁇ 1; ⁇ max (EtOH) 312nm ( ⁇ m 18,465) ; ⁇ H (CDCl3) 7.25 (1H, s, 4′-H), 6.53 (1H, d, 3 ⁇ -H), 6.40 (1H, d, 4 ⁇ -H), 6.25 (1H, s, 2-H), 2.27 (3H, s, 15-H3), 1.24 (3H, d, 14-H3) and 0.93 (3H, d, 15-H3); m / z (rel. int.) 511 ( M +, 10%), 366 (4), 296 (8) and 269 (87) (Found: 511.1197. C23H30NO7Br requires 511.1206).
• N-[2-(3-Furyl)-2-oxoethyl]monamide (1.8g) was cyclised to give the required oxazole (0.625g, 36%) after chromatography on silica (methanol in dichloromethane eluent); ⁇ max (film) 3400 (br), 1705, 1500, 1380 and 1335cm ⁇ 1; ⁇ max (EtOH) 290nm ( ⁇ m 14,663); ⁇ H (CDCl3) 7.74 (1H, s, 2 ⁇ -H), 7.47 (1H, t, 4 ⁇ -H), 7.11 (1H, s, 4′-H), 6.61 (1H, d, 5 ⁇ -H), 6.24 (1H, s, 2-H), 2.29 (3H, s, 15-H3), 1.23 (3H, d, 14-H3) and 0.93 (3H, d, 1-H3); ⁇ C (CDCl3) 160.4 (C-1), 146.7 (C-3), 143.8 (C-2 ⁇
• the monamide (from (a) (0.63g) was cyclised according to the general procedure to give the title oxazole (0.43g, 71%); ⁇ max (CHCl3) 3400, 1650, 1580cm ⁇ 1; ⁇ max (EtOH) 313nm ( ⁇ m 21,600); ⁇ H (CD3OD) 0.95 (3H, d, J 7Hz, 17-H3), 1.20 (3H, d, J 6.5Hz, 14-H3), 2.28 (3H, s, 15-H3), 2.35 (3H, s, 5 ⁇ -Me), 6.15 (1H, singlet with fine coupling, 3 ⁇ -H), 6.20 (1H, broadened singlet, 2-H), 6.57 (1H, d, J 3Hz, 4 ⁇ -H) 7.20 (1H, s, 4′-H); ⁇ C (CD3OD) 12.3 (C-17), 13.4 (5 ⁇ - C H3), 19.7 (C-15), 20.3 (C-14), 33.0 (C-9
• the furanyloxazole (Example 20) was converted to the free acid (0.11g), suspended in dichloromethane (15ml) and triethylamine (0.035ml). Cooled to 5 o C and treated with isobutyl chloroformate (0.033ml). After 1.3 hours at 5 o C ammonia gas was bubbled through the reaction mixture for 2 minutes then stirred for 15 minutes before diluting with ethyl acetate. This organic phase was washed with water, brine, dried (MgSO4) and evaporated to give a crude product.
• 3-Azidoacetyl-2,5-dimethylfuran (0.43g, 2.4mmol) was dissolved in methanol (30ml) and 2 M hydrochloric acid (15ml) added. This mixture was hydrogenated in the presence of 5% palladium on charcoal (50mg) at room temperature and pressure for 12 minutes.
• 2-Acetyl--4-carbamoylfuran (1.5g, 9.8mmol) was suspended in dichloromethane (50ml), chilled to 5 o C and treated with triethylamine (2.73ml, 19.6mmol) and tri­chloroacetyl chloride (1.21ml, 10.8mmol). The mixture was stirred for 0.5 hours, diluted with dichloromethane and washed sequentially with 1 M sodium hydroxide, water, 1 M hydrochloric acid, brine then dried (MgSO4), evaporated and subjected to silica chromatography (gradient elution 30%-100% ethyl acetate-hexane).
• Hexamethylenetetramine (2.45g, 17.5mM) was added to a solution of 2-bromoacetyl-4-cyanofuran (3.75g, 17.5mM) in dichloromethane (35ml) and the mixture stirred at room temperature for 3h.
• the precipitated product was filtered off, washed and dried (6.2g); ⁇ max (KBr) 2245, 1705, 1573 and 1499cm ⁇ 1. This product was then suspended in methanol (15ml) and concentrated hydrochloric acid (7.5ml) added and the mixture stirred 1.5h at ambient temperature.
• Methyl 2-acetyl-5-furoate (1g, 6mmol) was dissolved in methanol (10ml) and a solution of potassium hydroxide (0.5g, 8.7mmol) in water (4ml) added. The resulting solution was warmed for 30min at 60 o C then cooled, acidified and extracted with ethyl acetate (x2). The combined extracts were washed with a small volume of saturated brine, dried (MgSO4) and evaporated to give a brown amorphous solid (0.92g, 99%); ⁇ max (KBr) 3500-2200, 1690, 1570 and 1510cm ⁇ 1.
• 2-Acetyl-5-carbamoylfuran (0.75g, 4.9mmol) was suspended in dichloromethane (25ml), chilled to 5 o C and treated with triethylamine (1.36ml, 9.8mmol) and tri­chloroacetyl chloride (0.61ml, 5.4mmol).
• the mixture was stirred for 0.5h, diluted with dichloromethane and washed sequentially with 1 M hydrochloric acid, water, aqueous sodium hydrogen carbonate, brine then dried (MgSO4), evaporated and subjected to silica chromato­graphy eluting with dichloromethane.
• the ⁇ -aminoketone (0.38g) thus formed was reacted with te isobutoxyformic anhydride of monic acid using the standard method to give the title monamide (0.57g, 60%); ⁇ max (CHCl3) 3420, 2230, 1700, 1660 and 1630cm ⁇ 1; ⁇ max (EtOH) 267 ( ⁇ m 18,300) and 220nm (14,500); ⁇ H (CD3OD) 0.95 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.5Hz, 14-H3), 2.16 (3H, s, 15-H3), 4.56 (2H, s, 1′-H), 5.88 (1H, s, 2-H), 7.48 (2H, s, 3 ⁇ -H and 4′-H); ⁇ C (CD3OD) 12.3 (C-17), 19.1 (C-15), 20.4 (C-14), 33.0 (C-9), 41.7 (C-8), 43.8 (C-4 and C
• Trimethylsilyl chloride (0.26ml, 2.1mM) was added to a solution of 5-(4-cyano-2-furyl)-2-(1-normon-2-yl)­oxazole (0.105g, 0.23mM) (Example 24) in dry RHF (10ml) and triethylamine (0.29ml, 2.1mM), containing a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 1h at 5 o C then filtered and evaporated.
• 2-Bromo-4-furoic acid (1.35g, 7.0mM) was dissolved in dichloromethane (20ml) at 5 o C and treated with tri­ethylamine (1.07ml, 7.7mM) followed by ethyl chloro­formate (0.57ml, 7.1mM). The reaction was stirred for 0.5h at 5 o C then treated with triethylamine (1.39ml, 10mM) followed by N,O-dimethylhydroxylamine hydro­chloride (0.70g, 7.2mM) and left for a further 2.0h. The reaction was diluted with dichloromethane, washed with water, dried (MgSO4) and evaporated.
• N-Methoxy-N-methyl-2-bromo-4-furamide (1.10g, 4.7mM) in dry THF (30ml) at 5 o C under argon was treated with methylmagnesium iodide (3M solution in ether, 1.86ml, 5.5mM) and the reaction stirred 1.5h. Saturated ammonium chloride solution was then added carefully until effervescence ceased and the mixture extracted with ethyl acetate, washed with brine (xl), dried and evaporated.
• methylmagnesium iodide 3M solution in ether, 1.86ml, 5.5mM
• the monamide [Example 27(i)] (0.094g, 0.2mM) was cyclised according to the general method.
• the title oxazole was the major product (0.045g, 46%) [the cyanofuranyloxazole (Example 27) was also isolated (0.01g, 10%)]; ⁇ max (CHCl3) 1660cm ⁇ 1; ⁇ max (EtOH) 240 ( ⁇ m 15,900) and 286nm (20,900); ⁇ H (CD3OD) 0.95 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.5Hz, 14-H3), 2.28 (3H, s, 15-H3), 3.89 (3H, s, OC H 3), 6.22 (1H, s, 2-H), 7.20 (1H, s, 3 ⁇ -H), 7.34 (1H, s, 4′-H) and 8.08 (1H, s, 5 ⁇ -H); ⁇ C (CD3OD) 12.3
• This aldehyde in a small volume of diethyl ether (10ml) was added to a Tollens solution containing silver nitrate (7.6g, 44mM) in water (75ml) + sodium hydroxide (7.6g) in water (75g) with concentrated ammonia (0.88g/ml) added until clear solution obtained, and the resulting mixture stirred in a stoppered flask 3.0h at ambient.
• Tetramethylguanidinium azide (0.58g, 3.6mM) was added to an ice-cooled solution of 2-bromoacetyl-4-methyl­furan (0.67g, 3.3mM) in dichloromethane (25ml) under argon. The mixture was stirred for 1.5h, reduced in volume and applied to a silica column (20g) eluting with 2:1 hexane:ethyl acetate.
• the monamide (0.43g, 0.92mM) was cyclised according to the general method to give the title oxazole (0.25g, 60%); ⁇ max (CHCl3) 1710, 1655 and 1580cm ⁇ 1; ⁇ max (EtOH) 233 ( ⁇ m 7,150) and 310nm ( ⁇ m 22,900); ⁇ H (CD3OD) 0.95 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.5H, 14-H3), 2.08 (3H, s, furan C H 3), 2.27 (3H, s, 15-H3), 6.22 (1H, s, 2-H), 6.57 (1H, s, 3 ⁇ -H), 7.24 (1H, s, 4′-H) and 7.36 (1H, s, 5 ⁇ -H); ⁇ C (CD3OD) 9.5 (furan C H3), 12.2 (C-17), 19.7 (C-15), 20.3 (C-14), 33.0 (C-9),

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Saccharide Compounds (AREA)
• Steroid Compounds (AREA)
• Sub-Exchange Stations And Push- Button Telephones (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (4)

Publications (3)

Family

ID=26295206

Family Applications (1)

Country Status (20)

Cited By (1)

Families Citing this family (3)

Family Cites Families (2)

• 1990
  • 1990-04-08 IL IL94051A patent/IL94051A0/xx unknown
  • 1990-04-10 CA CA002014263A patent/CA2014263A1/fr not_active Abandoned
  • 1990-04-10 AU AU53100/90A patent/AU623242B2/en not_active Ceased
  • 1990-04-10 EP EP90303850A patent/EP0399645B1/fr not_active Expired - Lifetime
  • 1990-04-10 IE IE901299A patent/IE901299L/xx unknown
  • 1990-04-10 AT AT90303850T patent/ATE113946T1/de not_active IP Right Cessation
  • 1990-04-10 HU HU902138A patent/HUT58327A/hu unknown
  • 1990-04-10 PH PH40353A patent/PH27481A/en unknown
  • 1990-04-10 ES ES90303850T patent/ES2064619T3/es not_active Expired - Lifetime
  • 1990-04-10 PT PT93718A patent/PT93718A/pt not_active Application Discontinuation
  • 1990-04-10 MA MA22063A patent/MA21804A1/fr unknown
  • 1990-04-10 DE DE69013980T patent/DE69013980T2/de not_active Expired - Fee Related
  • 1990-04-10 NZ NZ233273A patent/NZ233273A/xx unknown
  • 1990-04-10 NO NO90901630A patent/NO901630L/no unknown
  • 1990-04-11 JP JP2094170A patent/JPH02292284A/ja active Pending
  • 1990-04-11 FI FI901841A patent/FI901841A7/fi not_active Application Discontinuation
  • 1990-04-11 KR KR1019900005012A patent/KR900016198A/ko not_active Withdrawn
  • 1990-04-12 CN CN90102095A patent/CN1046332A/zh active Pending
  • 1990-04-12 PL PL28879490A patent/PL288794A1/xx unknown
  • 1990-04-12 PL PL28879390A patent/PL288793A1/xx unknown
  • 1990-04-12 PL PL28476090A patent/PL284760A1/xx unknown
  • 1990-04-12 PL PL28879290A patent/PL288792A1/xx unknown
• 1995
  • 1995-02-08 GR GR940403601T patent/GR3014971T3/el unknown

Also Published As

Similar Documents

Legal Events